Autoimmune disease is caused by a failure of the immune system to recognize the difference between healthy tissue and harmful substances in the body. The immune system attacks healthy tissue and causes damage that may affect one or more tissue type or organ. For example, type 1 diabetes (T1DM), also known as diabetes mellitus type 1, is an autoimmune disease in which cytotoxic T-lymphocytes (CTL) attack and destroy the insulin-producing beta cells (β-cells) in the pancreas. Current management of T1DM involves administration of insulin and various formulations of insulin. Currently, an estimated 80,000 children develop T1DM each year and approximately 3 million people have T1DM in the United States. Complications from T1DM include heart disease, stroke, kidney failure, foot ulcers, and diabetic retinopathy. In addition, insulin treatment can lead to low blood sugar, or hypoglycemia, which can result in coma and death. Another immune-mediated disease, graft versus host disease (GVHD), can occur after a tissue transplant or blood transfusion. GVHD develops when grafted donor cells recognize the recipient's cells as foreign and differentiate into CTL that attack a recipient's healthy cells. GVHD can cause a range of symptoms from mild to severe, including death.
Current immune-suppressing drug therapies for GVHD, T1DM, and other autoimmune disorders produce global immune suppression throughout the body in order to reduce the autoimmune activity of CTL. Such immune suppression results in undesirable side effects associated with general immune suppression including an increased risk of infection and certain cancers. Thus, conventional immunosuppressive treatments of autoimmune diseases fail to provide long-term remission without severe side effects.
Targeting T cells is a promising therapeutic strategy for the prevention or treatment of autoimmune diseases. The aryl hydrocarbon receptor (AhR) represents a potential drug target as a ligand-activated transcription factor that directly alters T cell differentiation without cytotoxicity. 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) is a potent AhR ligand. Studies with TCDD have shown that AhR signaling during the early stages of cluster of differentiation 4 positive (CD4+) T cell activation results in induction of CD4+ regulatory T cells (Treg cells or Tregs) and premature cessation of cluster of differentiation 8 positive (CD8+) effector CTL differentiation. Treating mice with TCDD has been shown to prevent or ameliorate several different types of autoimmune and allergic diseases supporting the therapeutic potential of the AhR pathway and AhR as a potential therapeutic target. However, TCDD has unfavorable pharmacological properties due to TCDD's high lipid solubility and resistance to metabolism, which leads to a TCDD half-life of approximately seven years in humans. Additionally, the notoriety of TCDD as an environmental toxicant is likely to limit TCDD's acceptance for pharmacologic uses.